N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N2-arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of the following applications: Serial Number 653,217 of January 28, 1976 Serial Number 713,486 of August 11, 1976 Serial Number 671,436 of March 29, 1976 Serial Number 703,704 of July 8, 1976

The Serial Number 671,436 is a divisional of Serial Number 622,390 filed October 14, 1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N² -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, which are of especial value in view of their outstanding antithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N² -(p-tolysulfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971). One family of compounds which have been found to be particulary useful as highly specific inhibitors of thrombin for the control of thrombosis is the N² -dansyl-L-arginine ester or amide. (Our pending U.S. Application Ser. No. 496,939, filed Aug. 13, 1974 now U.S. Pat. No. 3,978,045). However, there is a continuing need for a highly specific inhibitor of thrombin for the control of thrombosis, which exhibits lower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibit antithrombotic activity and even lower toxicity levels at the same relative potencies, as compared with the N² -dansyl-L-arginine ester or amide.

An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR1## or a pharmaceutically acceptable salt thereof, wherein R is ##STR2## wherein R₁ is -COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 or 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;

and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -C₂₀ dialkylamino,

and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₀ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof;

naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

5,6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

C₇ -C₁₂ aralkyl-9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

naphthoquinony, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, αs-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, IH-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.

An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR3## or a pharmaceutically acceptable salt thereof, wherein R is ##STR4## wherein R₁ is -COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 or 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;

and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -C₂₀ dialkylamino,

and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₀ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof;

naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

5,6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

C₇ -C₁₀ aralkyl -9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;

a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.

Also encompassed within this invention are pharmaceutically acceptable salts thereof.

This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo in mammals which comprises administering to a mammal a pharmaceutically(antithrombotically) effective amount of an N² -arylnaphthalenesulfonyl-L-argininamide or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides of the formula (I): ##STR5## wherein R is selected from the group consisting of ##STR6## wherein R₁ is selected from the group consisting of C₂ -C₁₀ alkyl, such as ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-proplthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like. hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3;l -chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like, -carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such as -carboxybenzyl, -carboxyphenethyl or the like, C₃ -C₁₀ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C₄ -C₁₀ cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally substituted with one or more C₁ -C₅ alkyl, such as methyl, ethyl, propyl, butyl, or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like 1, 4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups such as methoxy, ethoxy, propoxy butoxy or the like and tetrahydro-3-thenyl; R₂ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ -C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, or 5-indanyl; and n is an integer of 1, 2 or 3, ##STR7## wherein R₃ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl or the like, haloalkyl or 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like, α-carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such as α-carboxybenzyl, α-carboxyphenethyl or the like, C₃ -C₁₀ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C₄ - C₁₀ cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C₁ -C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like tetrahydro-2 (3 or 5) -pyranylmethyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, 1, 4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, and tetrahydro-3-thenyl; R₄ is selected from the group consisting of alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy, alkoxycarbonyl of 2-10 (preferably 2-5) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like, phenyl optionally substituted with one or more C₁ - C₅ alkyl, such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and ring subsituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R₅ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and m is an integer of 0, 1 or 2, ##STR8## wherein R₆ is --COOR₈ wherein R₈ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; each R₇ independently is hydrogen, alkyl of 1-10 (preferably 1-6)carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl, C₁ - C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like, C₂ - C₆ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or the like, or carboxy; p is an integer of 1 to 4; R₆ is substituted at the 2 or 3-position; and R₇ can be substituted at the 2, 3, 4, 5 or 6 -position, ##STR9## optionally substituted with one or more C₁ - C₅ alkyl, such as methyl, ethyl, propyl, butyl or the like, or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like wherein R₉ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and r is an integer of 1, 2, 3 or 4, ##STR10## wherein R₁₀ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; Z is selected from the group consisting of oxy (--O--),thio (--S--) and sulfinyl (--SO--); q is an integer of 0 or 1, and ##STR11## wherein R₁₁ is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and Ar is a phenyl, naphthyl, naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as -indacenyl, S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, pheoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1, 8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group each of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N, N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ - C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like;

or a 5, 6, 7, 8-tetrahydronaphthyl, C₇ - C₁₂ aralkyl, 9, 10-dihydroanthryl, 5, 6, 7, 8-tetrahydroanthryl, 9, 10-dihydrophenanthryl, 1, 2, 3, 4, 5, 6, 7, 8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1, 2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, 2, 3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3, 4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1, 2, 3, 4-tetrahydroquinolyl, or 1, 2, 3, 4-tetrahydroisoquinolyl groups each of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N, N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like, hydroxyalkyl or 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, oxo and phenyl optionally substituted with at least one hydroxy and/or C₁ - C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like.

Illustrative of suitable N² -arylsulfonyl-L-argininamides are those shown in the table below. In this table, the prior art reference cited in the second column discloses a method of preparation for the compound listed in the second column. The Example No listed in the last column refers to an Example of this application which discloses the details of a method by which the product compound of the fifth column of the table may be prepared.

    TABLE I         Product  or salt thereofArSO.sub.2 Cl or ArSO.sub.3 H Starting      material       ##STR12##        Preparation NO. (Literature reference) Amino acid ester Ar R Procedure              1       ##STR13##       ##STR14##       ##STR15##       ##STR16##       1  Ger. 1,123,315       2      ##STR17##       ##STR18##       ##STR19##       ##STR20##       1  Ger. 1,123,315       3      ##STR21##       ##STR22##       ##STR23##       ##STR24##       2  Ber. 54,102 (1921)       4      ##STR25##       ##STR26##       ##STR27##       ##STR28##       2  CA 23, 1897       5      ##STR29##       ##STR30##       ##STR31##       ##STR32##       2  CA 25, 5420       6      ##STR33##       ##STR34##       ##STR35##       ##STR36##       2  CA 22,413       7      ##STR37##       ##STR38##       ##STR39##       ##STR40##       2  J. Ger. Chem. 6,444(1936)       8      ##STR41##       ##STR42##       ##STR43##       ##STR44##       1  Compt. rend 218,973(1944)       9      ##STR45##       ##STR46##       ##STR47##       ##STR48##       2  CA 33 4227       10      ##STR49##       ##STR50##       ##STR51##       ##STR52##       2  Can. J. Chem 41,100(1963) 11       ##STR53##       ##STR54##       ##STR55##       ##STR56##       1  Compt. rend 218,973(1944)       12      ##STR57##       ##STR58##       ##STR59##       ##STR60##       2  CA 49,5414       13      ##STR61##       ##STR62##       ##STR63##       ##STR64##       1  Naturwisserschaften 49,57(1962)       14      ##STR65##       ##STR66##       ##STR67##       ##STR68##       1  Z. Chem. 3,426(1963)       15      ##STR69##       ##STR70##       ##STR71##       ##STR72##       1  Z. Chem. 3,426(1963)       16      ##STR73##       ##STR74##       ##STR75##       ##STR76##       1  Ger. 1,219,477       17      ##STR77##       ##STR78##       ##STR79##       ##STR80##       1  Kogyo. Kaga Ku. Zashi 62,703(1967)       18      ##STR81##       ##STR82##       ##STR83##       ##STR84##       1  J. Chem. Soc. 1970,2500       19      ##STR85##       ##STR86##       ##STR87##       ##STR88##       1  Ber 31,1663       20      ##STR89##       ##STR90##       ##STR91##       ##STR92##       1  Ber 26,906       21      ##STR93##       ##STR94##       ##STR95##       ##STR96##       1  Beilstein 11I,135       22      ##STR97##       ##STR98##       ##STR99##       ##STR100##       3  mp 88-9°       23      ##STR101##       ##STR102##       ##STR103##       ##STR104##       3  mp 80-2       24      ##STR105##       ##STR106##       ##STR107##       ##STR108##       3  mp 55°       25      ##STR109##       ##STR110##       ##STR111##       ##STR112##       1  Ger 56780 (CA68,127or       26      ##STR113##       ##STR114##       ##STR115##       ##STR116##       3  Helv. chem. Acta 46,72781963       27      ##STR117##       ##STR118##       ##STR119##       ##STR120##       2  Zhur Obehchei Klim 18,1459(1948)       28      ##STR121##       ##STR122##       ##STR123##       ##STR124##       2  Per 84,1254(1956)       29      ##STR125##       ##STR126##       ##STR127##       ##STR128##       1  CA.47,10519       30      ##STR129##       ##STR130##       ##STR131##       ##STR132##       1  CA.32,2938       31      ##STR133##       ##STR134##       ##STR135##       ##STR136##       1  Monatsh. 92,677(1961)       32      ##STR137##       ##STR138##       ##STR139##       ##STR140##       2  Conept.rend 198,2260(1934)       33      ##STR141##       ##STR142##       ##STR143##       ##STR144##       2  Compt. rend 198,2260(1934)       34      ##STR145##       ##STR146##       ##STR147##       ##STR148##       1  J. Am. Chem. Soc 58,717(1936)       35      ##STR149##       ##STR150##       ##STR151##       ##STR152##       3  Montash. 85,235(1954)       36      ##STR153##       ##STR154##       ##STR155##       ##STR156##       2  J. Chem. Eng. Data 12,610(1967)       37      ##STR157##       ##STR158##       ##STR159##       ##STR160##       2  J. Ger. Chem 10,1077(1940) 38       ##STR161##       ##STR162##       ##STR163##       ##STR164##       2  J. Pharm. Soc. Japan 73,1878(1953)       39      ##STR165##       ##STR166##       ##STR167##       ##STR168##       2  J. Pharm. Soc. Japan 76,103(1958) 40       ##STR169##       ##STR170##       ##STR171##       ##STR172##       1  J. Chem. Soc 1958,3830 41       ##STR173##       ##STR174##       ##STR175##       ##STR176##       2  J. Chem. Soc 1958, 1499 42       ##STR177##       ##STR178##       ##STR179##       ##STR180##       2 43       ##STR181##       ##STR182##       ##STR183##       ##STR184##       1  J. Chem Soc 1968, 687 44       ##STR185##       ##STR186##       ##STR187##       ##STR188##        1  J. Chem. Soc 1968,687       45      ##STR189##       ##STR190##       ##STR191##       ##STR192##       1  J. Chem. Soc 1968, 687       46      ##STR193##       ##STR194##       ##STR195##       ##STR196##       1  J. Chem. Soc. 1968, 687       47      ##STR197##       ##STR198##       ##STR199##       ##STR200##       3  J. Chem. Soc. 72, 4890(1950)       48      ##STR201##       ##STR202##       ##STR203##       ##STR204##       2  U.S. Pat. No. 2,476,541       49      ##STR205##       ##STR206##       ##STR207##       ##STR208##       2  Zhur Obschei Khem 23,842       50      ##STR209##       ##STR210##       ##STR211##       ##STR212##       2  Zhur Obschei Khem 23,842       51      ##STR213##       ##STR214##       ##STR215##       ##STR216##       2  J. Am. Chem. Soc. 75,2095(1853)       52      ##STR217##       ##STR218##       ##STR219##       ##STR220##       2  Brit 590,645(1747)       53      ##STR221##       ##STR222##       ##STR223##       ##STR224##       2  J. Org. Chem. 23,435(1958)       54      ##STR225##       ##STR226##       ##STR227##       ##STR228##       2  U.S. Pat. No. 2,768,669       55      ##STR229##       ##STR230##       ##STR231##       ##STR232##       2  Gazz. Chem. ital. 81,764(1959)       56      ##STR233##       ##STR234##       ##STR235##       ##STR236##       2 Pharm. Bull. (Japan)5,297(1954)       57      ##STR237##       ##STR238##       ##STR239##       ##STR240##       3  (Aldrich)       58      ##STR241##       ##STR242##       ##STR243##       ##STR244##       3  Pharmazie 20,549       59      ##STR245##       ##STR246##       ##STR247##       ##STR248##      2  J. Am. Chem. Soc. 71       60      ##STR249##       ##STR250##       ##STR251##       ##STR252##      1U.S. Pat. No. 2,656,354       61      ##STR253##       ##STR254##       ##STR255##       ##STR256##       1       62      ##STR257##       ##STR258##       ##STR259##       ##STR260##       2  J. pr [2]118, 75       63      ##STR261##       ##STR262##       ##STR263##       ##STR264##       2  Photophysik Photochem 58, 3 (1963)       64      ##STR265##       ##STR266##       ##STR267##       ##STR268##       2  J. Chem. 16, 1873       65      ##STR269##       ##STR270##       ##STR271##       ##STR272##       2  Ber., 86, 951 (1953)       66      ##STR273##       ##STR274##       ##STR275##       ##STR276##       2  Ber 86, 951 (1963)       67      ##STR277##       ##STR278##       ##STR279##       ##STR280##       2  Ber 86, 951 (1953) 68       ##STR281##       ##STR282##       ##STR283##       ##STR284##       2  Zhur Obschei Khim 30, 1218 (1960) 69       ##STR285##       ##STR286##       ##STR287##       ##STR288##       2  Zhur Obschei Khim 30, 1218 (1960)       70      ##STR289##       ##STR290##       ##STR291##       ##STR292##       2  Bull. Soc Chem France 1950, 466       71      ##STR293##       ##STR294##       ##STR295##       ##STR296##       2  Bull. Soc. Chem France 1950, 466       72      ##STR297##       ##STR298##       ##STR299##       ##STR300##       1  Zhur. Obschei Khim 22, 866 (1952)       73      ##STR301##       ##STR302##       ##STR303##       ##STR304##       2  Zhur Obschei Khim 22, 866 (1952)       74      ##STR305##       ##STR306##       ##STR307##       ##STR308##       2  Zhur Obschei Khim 22, 866 (1952)       75      ##STR309##       ##STR310##       ##STR311##       ##STR312##       2  Zhur Obschei Khim 23, 866 (1952)       76      ##STR313##       ##STR314##       ##STR315##       ##STR316##       2       77      ##STR317##       ##STR318##       ##STR319##       ##STR320##       2  CA 62, 14675G       78      ##STR321##       ##STR322##       ##STR323##       ##STR324##       2 CA 26 4723       79      ##STR325##       ##STR326##       ##STR327##       ##STR328##       2  Japanese Patent Published  39-26975       80      ##STR329##       ##STR330##       ##STR331##       ##STR332##       2 Japanese Patent Published  39-26975       81      ##STR333##       ##STR334##       ##STR335##       ##STR336##       2 J. Am. Chem. Soc. 57,1533(1935)       82      ##STR337##       ##STR338##       ##STR339##       ##STR340##       2 J. Am. Chem. Soc. 59,15338(1935)       83      ##STR341##       ##STR342##       ##STR343##       ##STR344##      2  CA 45 90636       84      ##STR345##       ##STR346##       ##STR347##       ##STR348##       2 Org. Synth II. 539       85      ##STR349##       ##STR350##       ##STR351##       ##STR352##      3 (No. 8)       86 "      ##STR353##       ##STR354##       ##STR355##       3       87 "      ##STR356##       ##STR357##       ##STR358##       6       88 "      ##STR359##       ##STR360##       ##STR361##      689 "       ##STR362##       ##STR363##       ##STR364##      3

Also illustrative of suitable N² -arylsulfonyl-L-argininamides are those shown in the table below. In this table, the Example No listed in the sixth column refers to the Example of this application by which the compound in the first column was prepared.

    Table 2       Compound       ##STR365##       Concentrationrequired toprolong thecoagulationtime by a Preparation      Elementary analysisUpper: Calculated (%) Sample  Addition factor of two      process m.p. Lower: Found (%) I.R. (KBr) No. Ar R moiety (μM) (Ex.      No.) (° C) C H N       (cm.sup.-1)                                                  1       ##STR366##       ##STR367##       -- 8 1 powder 52.7652.68 6.356.21 13.38 13.303,3603,1601,620 2 "       ##STR368##       1/2H.sub.2       SO.sub.3  1 134-6 52.2552.07 6.826.73 11.2910.89      ##STR369##       3 "       ##STR370##       -- 0.3 1 powder 53.6253.48 6.566.43 13.0312.98 3,3603,1401,622 4 "       ##STR371##       1/2H.sub.2       SO.sub.3  1 164-6 52.9852.69 7.006.98 11.0410.86      ##STR372##       5 "       ##STR373##       -- 2 1 powder 53.6253.43 6.566.51 13.0313.12 3,3603,1601,620 6 "       ##STR374##       1/2H.sub.2       SO.sub.3  1 " 52.9852.59 7.006.79 11.0410.89 3,3903,1701,7371,370 7 "       ##STR375##       -- 5 1 " 54.4354.38 6.766.79 12.7012.56 3,3503,1801,630 8 "       ##STR376##       1/2H.sub.2       SO.sub.3  1 195-6 53.6953.40 7.157.12 10.8010.56      ##STR377##       9 "       ##STR378##       -- 1.5 1 powder 55.2154.98 6.957.02 12.3812.47 3,3603,2001,622 10 "       ##STR379##       1/2H.sub.2       SO.sub.3  1 198-200 54.37 54.30 7.307.27 10.5710.36      ##STR380##       11 "       ##STR381##       --  1 powder 56.6456.41 7.307.17 11.8011.51 3,3603,1801,620 12 "       ##STR382##       1/2H.sub.2       SO.sub.3  1 172-174 55.6455.31 7.597.63 10.1410.18      ##STR383##       13 "       ##STR384##       -- 0.5 3 powder 51.2050.93 6.176.02 12.9812.63 3,3803,1801,630 14 "       ##STR385##       ##STR386##       1.5 3 185 47.6747.64 4.92 4.81 11.1211.12 3,3753,2001,740 15 "       ##STR387##       -- 2.5 3 powder 52.0752.21 6.376.04 12.6712.51 3,3803,2001,620 16 "       ##STR388##       --  3 " 53.6953.53 6.766.69 12.0412.383,3803,2001,740 17 "       ##STR389##       -- 2.5 1 " 52.9052.71 6.576.43 12.3412.46 3,3503,1601,640 18 "       ##STR390##       1/2H.sub.2       SO.sub.3 1 " 52.4052.16 6.967.13 10.5410.28      ##STR391##       19 "       ##STR392##       -- 5 1 " 52.0751.91 6.376.19 12.6512.38 3,3603,1601,620 20 "       ##STR393##       1/2H.sub.2       SO.sub.3  1 " 51.6851.43 6.826.66 10.7610.58      ##STR394##       21 "       ##STR395##       -- 4 1 " 52.9052.59 6.576.41 12.3412.16 3,3603,1601,640 22 "       ##STR396##       1/2H.sub.2       SO.sub.3  1 powder 52.9852.73 7.007.00 11.0410.82      ##STR397##       23       ##STR398##       ##STR399##       -- 4 4 " 51.2051.31 6.176.01 12.9812.67 3,3603,1801,610 24 "       ##STR400##       ##STR401##        4 225-7 47.6747.62 4.924.84 11.1211.18 3,3753,2001,742 25 "       ##STR402##       -- 2 1 powder 53.6253.58 6.566.48 13.0312.94 3,3803,2001,630 26 "       ##STR403##       1/2H.sub.2       SO.sub.3  1 224 52.9852.73 7.007.00 11.0410.82      ##STR404##       27       ##STR405##       ##STR406##       -- 15 1 powder 52.8952.77 6.576.80 12.3412.59 3,3803,2001,625 28 "       ##STR407##       1/2H.sub.2       SO.sub.3  1 " 52.3952.10 6.976.84 10.5410.21      ##STR408##       29 "       ##STR409##       --  1 powder 55.2055.00 6.956.81 12.3812.21 3,3603,1501,620 30 "       ##STR410##       1/2H.sub.2       SO.sub.3  1 " 54.3654.25 7.307.11 10.5710.81      ##STR411##       31       ##STR412##       ##STR413##       -- 0.5 1 " 54.4354.21 6.556.50 13.8013.79 3,3603,1801,632 32 "       ##STR414##       1/2H.sub.2       SO.sub.3  1 "53.6353.50 7.006.79 11.5811.40      ##STR415##       33 "       ##STR416##       --  1 " 51.8651.64 6.136.09 13.7513.84 3,3703,2001,625 34 "       ##STR417##       1/2H.sub.2       SO.sub.3  1 " 55.2155.11 6.956.76 12.3812.27      ##STR418##       35       ##STR419##       ##STR420##       -- 0.5 3 " 51.8651.72 6.136.11 13.7513.63 3,3703,1601,62036 "       ##STR421##       ##STR422##        3 158-160 47.9447.83 4.854.80 11.5111.43 3,3753,2001,740 37 "       ##STR423##       --  1 powder 53.5353.40 6.336.21 14.1914.04 3,3753,1501,620 38 "       ##STR424##       1/2H.sub.2       SO.sub.3 1 " 52.8652.77 6.836.66 11.8611.75 3,3803,2001,7401,370 39 "       ##STR425##       -- 0.5 1 " 54.4354.22 6.556.31 13.8013.59 3,3803,1501,620 40 "       ##STR426##       1/2H.sub.2 SO.sub.3  1 131-137(dec.) 53.6353.40 7.007.10 11.5811.40       ##STR427##       41 "       ##STR428##       --  1 powder 55.2655.21 6.766.65 13.4313.29 3,3501,630 42 "       ##STR429##       1/2H.sub.2 SO.sub.3  1 169-175(dec.) 54.3554.27 7.177.00 11.3211.08       ##STR430##       43       ##STR431##       ##STR432##       -- 2.5 1 powder 51.8651.77 6.136.00 13.7513.72 3,3653,2001,620 44 "       ##STR433##       1/2H.sub.2       SO.sub.3  1 " 51.4751.20 6.656.35 11.5411.24      ##STR434##       45 "       ##STR435##       --  1 " 54.4354.28 6.556.31 13.8013.70 3,3753,2001,622 46 "       ##STR436##       1/2H.sub.2       SO.sub.3  1 " 53.6353.53 7.007.08 11.5811.40 3,3803,2001,7401,370 47 "       ##STR437##        -- 1 " 52.7652.47 6.356.01 13.3813.09 3,3753,1801,620 48 "       ##STR438##       1/2H.sub.2       SO.sub.3  1 " 52.2452.00 6.826.55 11.2811.00 3,3803,2001,7401,368 49       ##STR439##       ##STR440##       0.5 H.sub.2 SO.sub.3  1189-191(dec.) 55.6855.36 6.336.35 10.4710.45      3,3603,1601,730 50 "       ##STR441##       -- 2.5 1 powder 56.7356.43 5.825.80 12.2512.19 3,3703,2001,615 51 "       ##STR442##       ##STR443##        1 132-135(dec.) 52.7852.61 5.175.15 10.2610.23 3,3603,1801,720 52 "       ##STR444##       --10 1 powder 57.4257.19 6.026.10 11.9611.73 3,3603,1601,620 53 "       ##STR445##       ##STR446##        1 157-158(dec.) 52.7852.63 5.175.14 10.2610.09 3,3803,2201,750 54 "       ##STR447##       -- 3.0 1 powder  57.4257.09 6.026.06 11.9611.74 3,3603,2001,590 55 "       ##STR448##       ##STR449##        1 155-157(dec.) 53.2553.13 5.305.21 10.1110.03 3,3803,1801,720 56 "       ##STR450##       -- 50 1 powder 58.0857.93 6.22 6.04 11.6811.54 3,200-3,380(broad)1,620      57       ##STR451##       ##STR452##       ##STR453##         1 153-156(dec.) 52.2852.14 5.034.98 10.4110.36 3,4003,0801,740 58 "       ##STR454##       -- 6.5 1 powder 56.7356.58 5.825.73 12.2512.14 3,000-3,400(broad)1,600      59       ##STR455##       ##STR456##       ##STR457##        1 144-148(dec.) 53.6753.69 5.265.24 10.4310.39 3,3603,2001,720 60 "       ##STR458##       -- 50 1 powder 59.0459.14 6.196.15 12.3012.28 3,040-3,360 (broad) 1,610      61 "       ##STR459##       ##STR460##        1 155-158(dec.) 53.1954.97 5.125.0610.5910.48 3,4003,2001,730 62 "       ##STR461##       -- 15 1 powder 58.3758.19 6.005.98 12.6112.49 3,300 (broad)1,640 63       ##STR462##       ##STR463##       ##STR464##        1 147-150(dec.) 59.1959.23 5.125.07 10.5910.54 3,4003,230 1,750 64 "       ##STR465##       -- 20 1 powder 58.3758.21 6.005.93 12.6112.46 3,200 (broad)1,620 65       ##STR466##       ##STR467##       --  1 " 60.2960.21 6.586.56 11.7211.64 3,3653,1701,730 66 "       ##STR468##       -- 2.0 1 " 57.6657.48 5.77 5.74 12.9312.84 3,3603,1601,610 67       ##STR469##       ##STR470##       -- 1 1 " 50.2550.45 5.956.01 13.3213.15 3,3501,6201,3801,150 68       ##STR471##       ##STR472##       1/2H.sub.2       SO.sub.3  1 " 50.4350.57 6.656.58 10.5010.71 3,3501,7451,6501,360 69 "       ##STR473##       -- 5 1 171-2 50.6050.51 6.196.30 12.2912.40 3,4001,6351,2601,160 70 "       ##STR474##       --  3 powder 55.4055.65 6.626.81 12.4312.19 3,2201,7501,64071 "       ##STR475##       -- 5 2 "53.8253.66 6.215.96 13.08 12.81 3,3501,6251,155 72       ##STR476##       ##STR477##       ##STR478##        2 192-193 49.5849.24 4.874.70 11.5611.85 3,2101,7471,638 73 "       ##STR479##       -- 3 2 powder 54.6456.88 6.186.31 13.8513.83 3,200 (broad)1,6201,150 74       ##STR480##       ##STR481##       -- 0.4 2 " 54.6354.50 6.426.09 12.7412.81 3,3701,6251,158 75       ##STR482##       ##STR483##       ##STR484##        2 188-190 50.1750.01 5.034.78 11.3811.56 3,2001,7401,635 76 "       ##STR485##       -- 0.15 2 powder 55.4755.49 6.406.33 13.9813.51 3,250 (broad)1,625 77       ##STR486##       ##STR487##       --  2 " 57.0256.81 6.816.91 12.7912.78 3,2001,7401,635 78 "       ##STR488##       --  2 powder 55.4755.31 6.406.68 13.4813.21 3,3501,6201,150 79       ##STR489##       ##STR490##       ##STR491##        2 222-3 49.8249.57 5.094.88 11.9911.68 3,2001,7451,630 80 "       ##STR492##       -- 0.35 2 powder 54.6354.55 6.426.42 12.7412.58 3,350 (broad)1,6201,150      81       ##STR493##       ##STR494##       ##STR495##        2 154-6 50.9251.28 5.375.21 10.6610.59 3,4001,7351,635 82 "       ##STR496##       --  2 powder 56.1356.11 6.806.85 12.1211.95 3,300 (broad)1,6101,255 83       ##STR497##       ##STR498##       ##STR499##        2 179-180 50.3850.34 5.235.18 10.8211.05 3,3801,7351,635 84 "       ##STR500##       --  2 powder 55.4055.71 6.626.48  12.43 12.53 3,3601,6201,150 85       ##STR501##       ##STR502##       ##STR503##        2 125(soften) 50.7350.58 5.185.11 11.1910.93 3,3801,7351,638 86 "       ##STR504##       --  2 powder 56.2656.41 6.616.48 13.1213.27 3,3601,6201,158 87       ##STR505##       ##STR506##      --  2 " 57.5057.56 7.157.08 11.5611.71 3,3302,9601,7401,640 88 "       ##STR507##       -- 0.5 2 " 56.1356.11 6.806.81 12.1211.96 3,4001,620 89 "       ##STR508##       --  2 " 57.5057.15 7.157.21 11.5611.62 3,3602,9601,735 90 "       ##STR509##       --  2 " 56.1356.21 6.806.81 12.1212.03 3,4001,6201,150 91 "       ##STR510##       --  2 " 54.6354.54 6.426.40 12.7412.68 3,3501,6201,150 92 "       ##STR511##       --  2 powder 56.1356.08 6.806.91 12.1212.08 3,2501,7401,640 93       ##STR512##       ##STR513##       --  2 " 57.0256.86 6.816.83 12.7912.68 3,2301,7401,650 94 "       ##STR514##       --  2 " 54.6354.59 6.426.38 12.7412.68 3,2501,6201,160 95       ##STR515##       ##STR516##       ##STR517##        2 161-163 48.9749.05 4.71 4.73 11.7611.58 3,3401,7381,635 96 "       ##STR518##       --  2 powder 53.8253.68 6.216.08 13.0812.85 3,3701,6351,2551,155 97       ##STR519##       ##STR520##       --  2 " 54.6454.58 6.186.09 13.8513.93 3,3701,6401,2601,155 98       ##STR521##       ##STR522##       ##STR523##        1 165-168(dec.) 51.9451.50 5.645.41 10.3410.10 3,3903,2201,740 99 "       ##STR524##       --  1 powder 56.1356.00 6.816.73 12.1212.01 3,350 (broad)1,640 100 "       ##STR525##       ##STR526##        1 178-181(dec.) 51.9452.24 5.645.60 10.3410.28 3,4003,2001,735 101 "       ##STR527##       --  1 powder 56.1356.28 6.816.59 12.1212.31 3,350 (broad)1,640 102       ##STR528##       ##STR529##       ##STR530##        1  162-165(dec.) 51.4351.28 5.505.21 10.5010.21 3,3703,2001,730 103 "       ##STR531##       --  1 powder 55.4055.28 6.626.32 12.4312.03 3,300 (broad)1,610 (broad)      104       ##STR532##       ##STR533##       ##STR534##        1 158-160(dec.) 52.7552.56 5.565.43 11.0410.97 3,4053,2201,740 105 "       ##STR535##       --  1 powder 56.2656.01 6.616.49 13.1313.21 3,320 (broad) 1,640 106 "       ##STR536##       ##STR537##        1 160- 163(dec.) 52.3352.03 5.605.30 10.6810.28 3,4003,2101,730 107 "       ##STR538##       --  1 powder 57.0257.39 6.816.21 12.7912.38 3,350 (broad)1,620 108       ##STR539##       ##STR540##       ##STR541##        1 152-155(dec.) 52.8352.53 5.735.72 10.5210.29 3,3903,2051,730 109 "       ##STR542##       --  1 powder 57.7357.51 7.007.23 12.4712.28 3,3701,630 110       ##STR543##       ##STR544##       ##STR545##        1 170-172(dec.) 51.4351.09 5.505.45 10.5010.28 3,3803,2201,740 111 "       ##STR546##       -- 5 1 powder 55.4055.30 6.626.28 12.4312.11 3,400-3,200(broad)1,600      112 "       ##STR547##       ##STR548##        1 155-158(dec.) 51.9452.29 5.645.63 10.3410.00 3,3803,2001,730 113       ##STR549##       ##STR550##       --  1 powder 56.1356.40 6.816.61 12.1212.00 3,200-3,400(broad)1,600 114      "       ##STR551##       --  1 " 54.6354.40 6.426.30 12.7412.50 3,200-3,400(broad)1,600 115 "       ##STR552##       ##STR553##        1 165-170(dec.) 50.8150.68 5.585.43 10.6410.31 3,3803,2001,740 116 "       ##STR554##       --  1 powder 54.4354.70 6.766.71 12.7012.35 3,4001,590 117 "       ##STR555##       ##STR556##        1 164-166 51.3351.60 5.715.38 10.4810.25 3,3603,2001,735 118 "       ##STR557##       -- 2.0 1 powder 55.21 55.00 6.956.30 12.3812.40 3,400-3,200(broad)1,570      119 "       ##STR558##       ##STR559##         1 168-172 52.7752.54 5.174.98 10.2610.21 3,3803,1801,740 120       ##STR560##       ##STR561##       -- 2.5 1 powder 57.4257.35 6.025.84 11.9612.00 3,350-3,160(broad)1,600      121 "       ##STR562##       ##STR563##       1 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730 122 "       ##STR564##       -- 1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,600 123 "       ##STR565##       ##STR566##        1 158-163(dec.) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740 124 "       ##STR567##       --  1 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200(broad)1,625 125       ##STR568##       ##STR569##       ##STR570##        1 160-163(dec.) 52.4452.39 5.765.58 10.1910.00 3,4003,200 1,740 126 "       ##STR571##       -- 4.5 1 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(broad)1,595      127       ##STR572##       ##STR573##       ##STR574##        1 160-165(dec.) 50.6250.39 5.405.28 11.1711.15 3,4003,2101,740128 "       ##STR575##       --  1 powder 54.4354.27 6.556.28 13.8013.59 3,2801,590 129       ##STR576##       ##STR577##       -- 5 1 " 52.0751.89 6.376.39 12.6512.51 3,3603,2001,600 130       ##STR578##       ##STR579##       -- 20 5 210-213 54.8654.72 7.337.21 14.5414.27 3,3501,630 131       ##STR580##       ##STR581##       --  5 120-130 55.7355.82 7.527.50 14.1314.01 3,3501,630 132       ##STR582##       ##STR583##       -- 105 108-110 52.1552.21 6.886.71 14.4814.52 3,300 (broad)1,630 133       ##STR584##       ##STR585##       -- 30 5 powder 58.23 58.01 6.456.35 13.5813.46 3,300 (broad)1,635 134       ##STR586##       ##STR587##       --  5 powder 58.9658.91 6.666.79 13.2213.15 3,200 (broad)1,635 135       ##STR588##       ##STR589##       --  5 " 55.7355.81 7.527.40 14.1314.10 3,300 (broad)1,630 136 "       ##STR590##       --  5 170-173 57.5657.41 7.547.39 13.4313.50 3,3351,630 137       ##STR591##       ##STR592##       --  5 powder 56.7856.85 7.357.29 13.8013.71 3,200 (broad)1,630 138       ##STR593##       ##STR594##       --  5 " 58.9658.79 6.666.51 13.2213.19 3,300 (broad)1,630 139       ##STR595##       ##STR596##       --  5 142-145 49.0748.90 5.495.38 13.6313.42 3,1501,620 140       ##STR597##       ##STR598##       --  5 powder 47.4747.29 5.435.31 12.5812.39 3,1501,630 141       ##STR599##       ##STR600##       --  5 powder 49.0749.12  5.495.28 13.6313.59 3,1501,630 142       ##STR601##       ##STR602##       --  5 123-130 57.0156.88 6.986.71 13.85 13.65 3,3001,635 143       ##STR603##       ##STR604##       -- 0.3 5 powder 56.1956.00 6.776.50 14.2514.00 3,3003,1501,630 144 "       ##STR605##       -- 0.2 5 " 53.5353.24 6.336.19 14.1913.99 3,300 (broad)1,630 145 "       ##STR606##       --  5 " 60.0957.79 6.166.02 12.9312.61 3,300 (broad) 1,630 146 "       ##STR607##       -- 14 5 " 58.7358.66 7.016.90 13.1712.91 3,3801.635 147       ##STR608##       ##STR609##       --  5 147-150 52.5952.31 6.106.01 14.6114.33 3,3801,640 148       ##STR610##       ##STR611##       --  5 powder 57.2356.98 6.616.33 13.9113.81 3,300 (broad)1,630 149       ##STR612##       ##STR613##       --  5 " 58.6958.79 5.715.55 13.6913.39 3,300 (broad)3,1501,630 150 "       ##STR614##       --  5 " 56.1955.95 6.776.58 14.2513.97 3,190 (broad)1,620 151       ##STR615##       ##STR616##       -- 20 5 130-135 53.5353.28 6.336.19 14.1913.97 3,3501,640 152       ##STR617##       ##STR618##       -- 10 5 152-157 54.4254.28 6.55 6.32 13.8013.59 3,3501,635 153       ##STR619##       ##STR620##       -- 4 5 powder 55.3655.10 6.976.76 16.1416.07 3,3801,630 154 "       ##STR621##       --  5 " 52.8652.71 6.566.29 16.0816.07 155       ##STR622##       ##STR623##       --  5 powder 50.9050.81 5.905.70 14.1313.89 3,180 (broad)1,630 156       ##STR624##       ##STR625##       --  5 " 59.4159.22 5.955.73 13.3313.28 3,170 (broad)1,620 157 "       ##STR626##       HCl  6 " 53.1752.89 6.696.52  12.9212.74 158 "       ##STR627##       HCl  6 " 57.6657.31 6.346.14 11.5911.16 159 "       ##STR628##       --  5 " 55.3355.26 6.546.62 14.6714.58 3,200 (broad)1,630 160       ##STR629##       ##STR630##       -- 0.25 1 " 55.4755.75 6.406.19 13.4813.26 3,350 (broad)1,6301,380 161      "       ##STR631##       -- 0.2 5 " 55.0555.28 7.127.00 13.3813.12 3,200 (broad)1,6351,380 162       ##STR632##       ##STR633##       -- 0.2 1 powder 54.2253.98 5.505.55 13.1813.24 3,320 (broad)1,6301,380      163 "       ##STR634##       --  1 " 57.2257.23 6.356.36 11.9212.08 3,400 (broad)1,7401,620 164 "       ##STR635##       -- 0.15 1 " 53.8253.78 6.216.19 13.0812.86 3,360 (broad)1,6251,380 165      "       ##STR636##       --  1 " 56.8356.95  6.986.83 11.8411.98 3,400 (broad)1,7351,630 166       ##STR637##       ##STR638##       CH.sub.3 CO.sub.2       H  5 " 53.2853.13 6.626.82 13.8113.71 3,320 (broad)1,6301,140 167       ##STR639##       ##STR640##       --  5 " 51.1550.86 5.605.66 12.9712.87 3,320 (broad)1,6301,380 168       ##STR641##       ##STR642##       --  5 " 54.6453.36 6.186.00 13.8513.58 3,350 (broad)1,6401,390 169       ##STR643##       ##STR644##       --  5 powder 56.2755.98 6.616.78 13.1213.24 3,350(broad)1,6301,3801,140      170       ##STR645##       ##STR646##       --  5 " 54.2154.36 6.926.93 13.7413.76 3,300 (broad)1,6251,3801,160 171       ##STR647##       ##STR648##       --  1, 2 " 53.0852.86 6.246.33 12.3812.41 3,300 (broad)1,6401,160 172 "       ##STR649##       --  1 " 56.0255.83 6.976.88 11.2711.28 3,400 (broad)1,7451,620 173       ##STR650##       ##STR651##       -- 0.2 3 " 57.2356.89 6.616.50 13.9113.70 3,390 (broad)1,625 174 "       ##STR652##       CH.sub.3       COOH  3 " 56.8356.72 6.986.81 11.8411.56 3,400 (broad)1,7351,640 175 "       ##STR653##       -- 0.1 2 " 58.7358.52 7.016.77 13.1713.00 3,380 (broad)1,620176 "       ##STR654##       1/2H.sub.2       SO.sub.3  2 " 55.9855.69 7.057.21 11.6611.38 3,400 (broad)1,7301,635      177       ##STR655##       ##STR656##       --  3 " 58.7358.81 7.027.03 13.1713.17 3,300 (broad)1,6151,380 178 "       ##STR657##       CH.sub.3       COOH  3 " 58.1357.98 7.327.56 11.3011.28 3,380 (broad)1,7301,630 179       ##STR658##       ##STR659##       -- 1 3 " 56.4256.38 6.386.52 14.3114.53 3,350 (broad) 1,6201,160 180 "       ##STR660##       CH.sub.3       COOH  3 " 56.1356.08 6.806.83 12.1212.12 3,400 (broad)1,7401,630 181       ##STR661##       ##STR662##       -- 0.5 3 " 58.0057.83 6.826.77  13.5313.63 3,350 (broad)1,6201,160 182      "       ##STR663##       CH.sub.3       COOH  3 " 57.5057.61 7.157.11 11.5611.81 3,350 (broad)1,7301,620 183       ##STR664##       ##STR665##       -- 0.35 3 " 55.5855.62 6.61 6.81 16.2116.03 3,350 (broad)1,6201,140 184       ##STR666##       ##STR667##       --  3 " 55.9656.12 7.157.28 14.1914.07 3,350 (broad)1,6201,150 185 "       ##STR668##       CH.sub.3       COOH  3 " 55.7455.90 7.457.51 12.0412.18 3,400 (broad)1,7301,625 186       ##STR669##       ##STR670##       --  3 " 54.3854.08 6.215.91 12.6912.39 3,300 (broad)1,625 187       ##STR671##       ##STR672##       --  2 " 52.2552.36 6.035.98 12.7012.51 3,4001,7351,6401,160 188 "       ##STR673##       --  2 " 50.4650.61 5.585.63 13.3813.40 3,3801,6201,3801,155 189 "       ##STR674##       -- 2 3 " 52.0652.31 5.765.81 13.8013.51 3,3201,6201,3901,155 190 "       ##STR675##       -- 2 " 48.9649.13 5.425.38 12.9812.75 3,3501,6201,3801,150 191       ##STR676##       ##STR677##       -- 5 2 " 51.38 51.45 5.815.86 13.0313.12 3,3501,6301,2551,150 192       ##STR678##       ##STR679##       --  2 " 49.5049.31 5.345.40 13.7513.68 3,3503,2001,622 193       ##STR680##       ##STR681##       --  2 " 58.2758.45 5.906.03 11.7211.53 3,3501,7401,6401,2601,160 194 "       ##STR682##       -- 2 2 " 57.6257.68 5.705.55 12.0011.73 3,300 (broad)1,6201,2501,150      195 "       ##STR683##       -- 1.5 3 " 56.9357.12 5.495.43 12.3012.14 3,3601,6251,2601,150 196 "       ##STR684##       -- 6.5 1 " 54.6354.28 6.426.31 12.7412.53 3,350 (broad)1,740 197 "       ##STR685##       --  2 " 53.8654.16 5.925.62 13.0012.70 3,100 (broad)1,620 198 "       ##STR686##       1/2H.sub.2 SO.sub.3  2 " 54.5354.23 6.105.80 9.649.34 1,7201,630      (broad) 199       ##STR687##       ##STR688##       --  2 " 48.5548.31 4.934.64 11.8011.53 3,300 (broad)1,620 200       ##STR689##       ##STR690##       HCl 2 6 " 54.1053.81 7.327.13 10.18 9.93 3,180 (broad)1,7401,630 201 "       ##STR691##       --  2 " 57.2256.98 6.246.18 11.1211.31 3,3003,1501,7401,650 202 "       ##STR692##       HCl 20 6 " 54.0953.83 6.055.97 10.5110.36 3,2503,1001,7401,640 203 "       ##STR693##        HCl 30 6 " 55.5355.37 6.126.01 10.1210.01 3,3503,1501,7401,650 204       ##STR694##       ##STR695##       -- 4.5 2 " 48.9649.13 5.425.36 12.9813.01 3,3501,6201,380 205 "       ##STR696##       -- 2.5 2 " 54.6454.63 6.426.56 12.7413.01 3,3602,9401,6201,380 206       ##STR697##       ##STR698##       -- 12 2 " 59.8959.65 4.524.63 11.6411.81 3,3601,6201,2551,150 207 "       ##STR699##       -- 55 2 " 50.1549.91 6.416.35 14.0413.83 3,2801,620 208 "       ##STR700##       --  2 " 53.8553.61 5.935.76 13.0012.84 3,3201,610 209 "       ##STR701##       -- 2 2 " 57.4257.37 6.025.86 11.9611.74 3,300 (broad)1,600 210       ##STR702##       ##STR703##       --  2 " 57.4157.33 6.035.94 11.9611.73 3,3001,610 211 "       ##STR704##       -- 2.5 2 " 53.9853.74 5.385.33 11.6611.74 3,3501,630 212       ##STR705##       ##STR706##       -- 6.5 2 " 52.0652.40 6.386.37 12.6512.73 3,350 (broad)1,620 213 "       ##STR707##       --  2 " 52.0751.95 6.376.27 12.6512.84 3,350 (broad)1,620 214 "       ##STR708##       -- 15 2 " 52.7552.68 6.366.34 13.3813.41 3,380 (broad)1,620 215 "       ##STR709##       --  2 " 50.9750.67 6.586.61 13.7213.39 3,200 (broad)1,610 (broad) 216 "       ##STR710##       1/2H.sub.2 SO.sub.3  2 " 52.0151.77 6.696.50 10.1110.00 1,7251,620 217       ##STR711##       ##STR712##       --  5 " 46.8146.63 6.005.94 14.3714.23 3,4003,3001,630 218       ##STR713##       ##STR714##       --  5 " 51.3851.24 5.825.79 13.0312.87 3,3803,3001,630 219       ##STR715##       ##STR716##       --  1 " 52.1552.03 6.886.73 14.4814.68 3,3551,6301,3801,305 220       ##STR717##       ##STR718##       2H.sub.2 O 2 2 195-198 50.4250.48 6.546.16 12.2512.31 3,3201,620 221 "       ##STR719##       1/2H.sub.2 O 15 2 229-233 52.9452.73 6.306.15 12.8712.93 3,3501,620 222       ##STR720##       ##STR721##       -- 6.5 1 powder 48.7848.54 5.775.76 12.9313.15 3,3201,6201,390 223       ##STR722##       ##STR723##       --  1 " 50.2750.11 5.955.87 13.3313.34 3,3901,6301,2601,160 224       ##STR724##       ##STR725##       --  5 " 53.7653.66 5.955.83 14.2514.19 3,4003,2001,635 225       ##STR726##       ##STR727##       --  5 " 46.6246.53 6.386.21 14.3114.43 3,3503,1501,630 226       ##STR728##       ##STR729##       --  5 " 49.7149.84 7.027.26 13.1813.36 3,250 (broad)3,1501,630 227 "       ##STR730##       --  5 " 46.2446.31 6.406.53 13.4813.41 3,3203,1501,630 228       ##STR731##       ##STR732##       HCl  1 " 47.7447.53 6.756.51 14.6514.41 3,3403,1801,640 229       ##STR733##       ##STR734##         1  52.9552.79 6.005.87 13.4313.28 3,3503,1501,620 230 "       ##STR735##         1  53.16 5.64 13.48 231       ##STR736##       ##STR737##         5  40.7140.60 4.954.78 13.1913.03 3,3603,1501,620 232       ##STR738##       ##STR739##       --  3 " 55.5955.54 6.296.14 12.4712.35 3,3503,1501,625 233       ##STR740##       ##STR741##       --  3 " 57.4357.26 6.136.04 12.8812.71 3,3503,1301,615 234       ##STR742##       ##STR743##       --  5 " 46.80 46.61 6.116.05 15.1615.23 3,3753,1501,630 235       ##STR744##       ##STR745##       --  3 " 50.8250,71 6.866.69 12.8912.57 3,3603,1201,620

The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention.

For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is possible by way of several synthetic routes which are outlined below.

a. Condensation of an L-argininamide with an arylsulfonyl halide This process may be illustrated as follows: ##STR746## In the above formulas, R and Ar are as defined herein above; X is halogen; R'" is a protective group for the α-amino group, such as benzyloxycarbonyl or tertbutoxycarbonyl; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl and the like; and at least one of R' and R" is a protective group for the guanidino group. The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an L-argininamide (VI) with a substantially equimolar amount of an arylsulfonyl halide (VII), preferably a chloride.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), at a temperature of 0° C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

The preferred solvents for the condensation include benzene-diethyl ether, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N² -arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ethertetrahydrofuran, diethyl ether-methanol and watermethanol, or may be chromatographed on silica gel. The L-argininamides (VI) starting materials required for the condensation reaction can be prepared by protecting the guanidino and α-amino groups of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N^(G) -substituted-N² -substituted-L-arginine (III) with a corresponding amino acid derivative (IV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the formed N^(G) -substituted-N² -substituted-L-argininamide (V). The amino acid derivatives (IV) which are the starting materials for the preparation of the N^(G) -substitutedN² -substituted-L-argininamides (V) are represented by the following formulas: ##STR747## In the above formulas, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, Z, n, m, r, q, i, and j are as defined herein above.

The amino acid derivatives of the above formula (VIII) or (IX) can be prepared by the condensation of a haloacetate, 3-halopropionate or 4-halobutyrate with an appropriate amine having the formula R₁ NH₂ or R₃ NH₂. (See, J. Org. Chem., 25 728-732 (1960)). The condensation reaction is generally carried out without a solvent or in a solvent, such as benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of 0° C to 80° C for a period of 10 minutes to 20 hours. After the reaction is complete, the formed amino acid derivative is separated by such conventional means as extraction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure.

Among the amino acid derivatives, amino acid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in the presence of a corresponding alcohol employing an inorganic acid (HCl, H₂ SO₄, etc.) or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). In accordance with the process employed for preparing 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative: ##STR748## In the first reaction of the aforementioned scheme, an appropriately substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5° C to 0° C. The resultant product (XV) is isolated by extraction with a solvent, e.g., diethyl ether, and then treated with potassium hydroxide in a lower alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2-dehydropiperidines (XVI) to the corresponding 2-cyano analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids (XVIII) is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.

The arylsulfonyl halides (VII) which are the starting materials for the preparation of the N² -arylsulfonyl-L-argininamides (I) can be prepared by halogenating the requisite arylsulfonic acids or their salts, e.g., sodium salts, by conventional methods well known to those skilled in the art.

In practice, halogenation is carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, at a temperature of -10° C to 200° C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene or the like.

b. Removal of the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide

This process may be illustrated as follows: ##STR749##

In the above formulas, R, Ar, X, R', R" and R'" are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide (XX) by means of acidolysis or hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G) -substituted-N² -arylsulfonyl-L-argininamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -10° C to 100° C, and preferably at room temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of the excess acid, the products are generally the acid addition salts of the N² -arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis. At the same time, the benzyl ester moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0° C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure is sufficient.

The N² -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.

The N² -arylsulfonyl-L-argininamides can be purified in the same manner as described above.

The N^(G) -substituted-N² -arylsulfonyl-L-argininamides (XX) starting materials can be prepared by condensing an N^(G) -substituted-N² -substituted L-arginine (III) (generally the N^(G) -substituent is nitro or acyl, and the N² -substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV), selectively removing only the N² -substituent of an N^(G) -substituted-N² -substituted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained N^(G) -substituted-L-argininamide (XIX) with an arylsulfonyl halide (VII), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with an arylsulfonyl halide, and the removal of the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide.

c. Condensation of an N² -arylsulfonyl-L-arginyl halide with an amino acid derivative

This process may be illustrated as follows: ##STR750##

In the above formulas, R, Ar and X are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an N² -arylsulfonyl-L-arginyl halide (XXII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV). The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginyl halide (XXII).

Preferred condensation reaction temperatures are in the range of from -10° C to room temperature. The reaction time is not critical, but varies with the amino acid derivative (IV) employed. In general, a period of from 5 minutes to 10 hours is operable. The obtained N² -arylsulfonyl-L-argininamide can be isolated and purified in the same manner as described above.

The N² -arylsulfonyl-L-arginyl halide (XXII) starting materials required for the condensation reaction can be prepared by reacting an N² -arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorous tribromide. The halogenation can be carried out with or without an added solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginine (XXI).

Preferred reaction temperature are in the range of -10° C to room temperature. The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.

The N² -arylsulfonyl-L-arginines (XXI) which are the starting materials for the preparation of the N² -arylsulfonyl-L-arginyl halides (XXII) can be prepared by the condensation of L-arginine (II) with a substantially equimolar amount of arylsulfonyl halides (VII), by a method similar to that described in the condensation of an L-argininamide with an arylsulfonyl halide.

d. Guanidylation of an N² -arylsulfonyl-L-ornithinamide or an acid addition salt thereof

This process may be illustrated as follows: ##STR751## In the above formulas, R and Ar are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by guanidylating an N² -arylsulfonyl-L-ornithinamide (XXIII) with an ordinary guanidylating agent such as an O-alkylisourea, S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² -arylsulfonyl-L-ornithinamide (XXIII) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0° C to the boiling temperature of the solvent for a period of from 30 minutes to 50 hours.

Examples of the preferred bases are triethylamine, pyridine, sodium hydroxide and sodium methoxide. The base is used in an amount of 0.01 to 0.1 equivalent to the N² -arylsulfonyl-L-ornithinamide.

Examples of the preferred solvents are water, water-ethanol and water-dioxane.

After the reaction is complete, the N² -arylsulfonyl-L-argininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.

It is well recognized in the art that an ester derivative of the N² -arylsulfonyl-L-argininamide (I) wherein R₂, R₅, R₈, R₉, R₁₀ or R₁₁ is alkyl, aralkyl, aryl or 5-indanyl, can be prepared from a carboxylic acid derivative of the N² -arylsulfonyl-L-argininamide wherein R₂, R₅, R₈, R₉, R₁₀ or R₁₁ is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N² -arylsulfonyl-L-argininamides containing a free carboxyl group, wherein R₂, R₅, R₈, R₉, R₁₀ or R₁₁ is hydrogen, forms salts with any of a variety of inorganic and organic bases.

The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. In a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in a regeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity in mammals against thrombim as well as by their substantial lack of toxicity, and therefore these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor of platelet aggregation.

The antithrombotic activity of the N² -arylsulfonyl-L-argininamide of this invention was compared with that of a known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows:

An 0.8 ml. aliquot of a fibrinogen solution, which had been prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.

Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25° C. Coagulation times were taken as the period between the time of transference to the 25° C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds. The experimental results are summarized in Table 2. The term "concentration required to prolong the coagulation time by a factor of two" is the concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100μm. The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.

When a solution containing an N² -naphthylsulfonyl-L-argininamide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from 1 to 3 hours. The halflife for decay of the anti-thrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions of the host animals (rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitoneal administration of substances of formula (I) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight.

Representative LD₅₀ values for the compounds of this invention are shown in the following Table.

    ______________________________________                                         Compound                 LD.sub.50 (mg/kg)                                     ______________________________________                                         N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                      arginyl-N-butylglycine   >1,500                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-methoxyethyl)glycine                                                                       1,900-2,400                                           N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-ethoxyethyl)-β-alanine                                                                660-1,000                                             N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-methoxyethyl)glycine                                                                       660-1,000                                             N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-                                     arginyl-N-(2-methoxyethyl)glycine                                                                       2,000                                                 N.sup.2 -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-                              L-arginyl-N-(2-methoxyethyl)glycine                                                                     >1,500                                                N.sup.2 -(6,7-dimethyl-1-naphthylsulfonyl)-L-                                  arginyl-N-(2-methoxyethyl)glycine                                                                       >1,500                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-ethylthioethyl)glycine                                                                     >1,000                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-benzylglycine  >1,000                                                N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-benzylglycine  >1,000                                                N.sup.2 -(5-methoxy-1-naphthylsulfonyl)-L-                                     arginyl-N-benzylglycine  >1,000                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-phenethylglycine                                                                              >1,500                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-cyclohexylglycine                                                                             >1,500                                                N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-cyclohexylmethylglycine                                                                       >1,500                                                N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                      arginyl-N-tetrahydrofurfurylglycine                                                                     600                                                   N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-tetrahydrofurfurylglycine                                                                     620                                                   N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-butylalanine   >1,500                                                N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-cyclohexylmethylalanine                                                                       >1,500                                                1-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                              arginyl]-2-piperidinecarboxylic acid                                                                    1,500                                                 Ethyl[1-N.sup. 2 -(7-methoxy-2-naphthylsulfonyl)-                              L-arginyl]-4-methyl-2-piperidinecarboxylate                                                             670-1,000                                             1-[N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-                                L-arginyl]-4-methyl-2-piperidinecarboxylic                                                              670-1,000                                             acid                                                                           1-[N.sup.2 -(1-naphthylsulfonyl)-L-arginyl] -4-                                methyl-2-piperidinecarboxylic acid                                                                      700-1,000                                             1-[N.sup.2 -(5-dimethylamino-1-naphthylsulfonyl)-                              L-arginyl]-2-piperidinecarboxylic acid                                                                  700-1,000                                             4-[N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-                                  arginyl]-3-morpholinecarboxylic acid                                                                    >1,000                                                2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                              arginyl]-1,2,3,4-tetrahydroisoquinoline-3-                                     carboxylic acid          >1,000                                                2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                              arginyl]-1-isoindolinecarboxylic acid                                                                   >1,000                                                ______________________________________                                    

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide and N² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams per kilogram, respectively.

The therapeutic agents in this invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable for humans, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment. When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kg orally per day.

Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

It is to be understood that the present invention includes pharmaceutical compositions containing a compound of the invention as an active ingredient. Such compositions may be in the forms described above. In particular, the invention includes such compositions in unit dose form.

EXAMPLE 1 A. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine:

To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10% potassium carbonate solution was added 114.7 g of 6,7-dimethoxynaphthalenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 60° C for 5 hours, during which time the product precipitated. After 1 hour at room temperature, the precipitate was filtered and washed successively with benzene and water to give 129 g (76 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine, M.P. 252°-5° C.

B. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride

A suspension of 2.00 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride.

C. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester

To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for 1 hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164-166° C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm⁻¹.

Analysis -- Calcd. for C₂₈ H₄₃ O₇ N₅ S.1/2H₂ SO₃ (percent): C, 52.98; H, 7.00; N, 11.04 Found (percent): C, 52.69; H, 6.98; N, 10.86

D. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine

To a solution of 2.00 g of N² -(6,7-dimethoxy-2-naphthylsulfonly)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatograhed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.43 g (79 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid, I.R. (KBr): 3,360, 3,140, 1,622 cm⁻¹.

Analysis -- Calcd. for C₂₄ H₃₅ N₅ O₇ S (percent): C, 53.62; H, 6.56; N, 13.03 Found (percent): C, 53.48; H, 6.43; N, 12.98

The following compounds are prepared in a similar manner:

N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-butyl-β-alanine

N² -(7-methyl-2-naphthylsulfonyl)-N-(2-methoxyethyl)-N-(3-carboxypropyl)-D-argininamide

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(5-methoxy-1-naphthysulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine tert-butyl ester

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)-β-alanine

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methylthioethyl)-N-(3-carboxypropyl)-L-argininamide

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(3-methylthiopropyl)glycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)-β-alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine benzyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropyl)-L-argininamide

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylglycine

4-N-[N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-N-cyclohexylaminobutyric acid

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethyl-β-alanine

N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenylpropyl)glycine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-benzyl-β-alanine

N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N² -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl-β-alanine

N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl-β-alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylalanine

N² -(7-methoxy-2-naphthylsulfonly)-N-(3-carboxypropyl)-N-tetrahydrofurfuryl-L-argininamide

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-isobutylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenylpropyl)alanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylbutyrine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-furylmethyl)glycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-aryginyl-N-(tetrahydro-3-furylmethyl)glycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-thenyl)glycine N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-thenyl)glycine N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-thenyl)glycine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-)Tetrahydro-3-thenyl)glycine

N₂ -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-acetylethyl)glycine

N₂ -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfuryl)glycine

N₂ -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine

N₂ -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(1,4-diacyclohexylmethyl)glycine

1-(N₂ -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-4-methoxy piperidine-2-carbonxylic acid

1-(N₂ -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl)-5-methylhexamethyleneimine-2-carbonxylic acid

1-(N₂ -(3,7-dimethyl-2-dibenzofluranyl)-L-arginyl)-4,4-dimethyl-2-piperidine carboxylic acid

N₂ -(3-methoxy-5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-pyranylmethyl)glycine

EXAMPLE 2 A. N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride.

A suspension of 2.5 g of N² -(6-methoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride.

B Ethyl 1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate

To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate. For analysis of the product, a portion of the product was converted to the flavinanate, M.P. 192°-3° C. I.R. (KBr): 3,210, 1,747, 1638 cm⁻¹

Analysis -- Calcd. for C₂₅ H₃₅ 0₆ N₅ S.C₁₀ H₆ O₈ N₂ S (percent):

C, 49.58; H, 4.87; N, 11.56 Found (percent): C, 49.24;

H, 4.70; N, 11.85

C. 1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid

A solution of 2.8 g of ethyl 1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N-NaOH solution was warmed to 60° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200 -- 300 mesh, H³⁰ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH₄ OH (10:9:1). The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm⁻¹

Analysis -- Calcd. for C₂₃ H₃₁ O₆ N₅ S (percent):

C, 54.64; H, 6.18; N, 13.85 Found (percent):

C, 56.88; H, 6.31; N, 13.83

The following compounds are prepared in a similar manner;

N² -(6-chloro-2-naphthylsulfonyl)-L-arginyl-N-butylglycerine

N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)-glycine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethyl-β-alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-carboxypropyl)-L-argininamide

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylnorleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylisoleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylbutyrine

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cycloheptylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl-βalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)norvaline

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylleucine

1-[N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(5-ethoxy-1-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(7-ethoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-tert-butyl-2-piperidinecarboxylic acid

Phenyl 1-[N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylate

Benzyl 1-[N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylate

Benzyl 1-[N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate

1-(N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N² -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1-[N² -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid

1[N² -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid

1-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-6-methyl-2-piperidinecarboxylic acid

1-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-4-tertbutyl-2-piperidinecarboxylic acid

1-[N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl]indoline-2-carboxylic acid

2-[N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

4-(N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]thiomorpholine-3-carboxylic acid

4-[N² -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

4-[N² -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl]-3-carboxythiomorpholine 1-oxide

4-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

4-[N² -(7-chloro-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

4-[N² -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

4-[N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl]thiomorpholine-3-carboxylic acid

4-[N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl]thiomorpholine-3-carboxylic acid

4-[N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

Ethyl 4-[N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylate

4-[N² -(5-ethoxy-1-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylic acid

4-[N² (5-dimethylamino-1-naphthylsulfonyl)-L-arginyl]thiomorpholine-3-carboxylic acid

3-[N² -(1-naphthylsulfonyl)-L-arginyl]thiazolidine-4-carboxylic acid

2-[N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

2-[N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-[N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(5-ethoxy-1-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

EXAMPLE 3 A. N^(G) -nitro-N² -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:

To a stirred solution of 28.3 g of N^(G) -nitro-N² -(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while keeping the temperature at -5° C. After 15 minutes, to this was added 14.2 g of N-(2-methoxyethyl)glycine ethyl ester, and the mixture was stirred for 15 minutes at -5° C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was dissolved in 20 ml of chloroform, and the solution was applied to a column (80 cm × 6 cm) of 500 g of silica gel packed in chloroform. The product was eluted first the chloroform, and then 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to dryness to give 25.8 g (63 percent) of N^(G) -nitro-N² -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in the form of a syrup. I.R. (KBr): 3,300, 1,740, 1,690 cm⁻¹

B. N^(G) -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride

To a stirred solution of 29.8 g of N^(G) -nitro-N² -(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0° C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give 24.1 g of N^(G) -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride as an amorphous solid.

C. N^(G) -nitro-N² -(6.7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester

To a stirred solution of 4.0 g of N^(G) -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodium bicarbonate, and 3.5 g of 6,7-dimethoxy-2-naphthalensulfonyl chloride in 30 ml of dioxane at 5° C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the residue dissolved in 40 ml of chloroform, and washed with 10 ml of 1N hydrochloric acid solution and 20 ml of water. The chloroform solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chlorofrom and eluted with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 5.3 g (87 percent) of N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in the form of an amorphous solid. I.R. (KBr): 3,240, 1,740, 1,630 cm⁻¹

D. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester

To a solution of 3.00 g of N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 2.53 g (91%) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester. For analysis of the product, a portion of the product was converted to the flavianate; M.P. 185° C, I.R. (KBr): 3,375, 3,200, 1,740 cm⁻¹.

Analysis -- Calcd. for C₂₅ H₃₇ N₅ O₈ S.C₁₀ H₆ N₂ O₈ S (percent):

C, 47.67; H, 4.92; N, 11.12 Found (percent):

C, 47.64; H, 4,81; N, 11.12

E. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

A solution of 2.5 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 5 ml of ethanol and 7 ml of 1N sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200 - 300 mesh, H⁺ form manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-ethyl ester to give 1.32 g (72 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid. I.R. (KBr): 3,380, 3,180, 1,630 cm⁻¹

Analysis -- Calcd. for C₂₃ H₃₃ N₅ O₈ S (percent): C, 51.20;

H, 6.17; N, 12.98 Found (percent): C, 50.93;

H, 6.02; N, 12.63

The following compounds are prepared in a similar manner:

N² -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glycin

N² -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

N² -(7-ethyl-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-cyclohexylglycine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-cyclohexyl)propylglycine

2-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-[N² -methyl-2-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(2-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-[N² -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(5-chloro-1-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

1-[N² -(5-hydroxy-1-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroquinoline-2-carboxylic acid

2-[N² -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl]isoindoline-1-carboxylic acid

2-[N² -(1-naphthylsulfonyl)-L-arginyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

EXAMPLE 4 A. L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride

To a solution of 4.0 g of N^(G) -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 150 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 3.0 g (81%) of L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in the form of a powder.

B. N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester

To a well stirred solution of 2.00 g of L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride and 1.95 g of K₂ CO₃ in 20 ml of water and 10 ml of dioxane was added dropwise a solution of 2.17 g of 4,6-dimethoxy-2-naphthalanesulfonyl chloride in 30 ml of dioxane over a period of 30 minutes while maintaining the temperature at 0° C. The reaction mixture was stirred for an additional 5 hours at room temperature. At the end of this period, the solvent was evaporated and the residue taken up in 50 ml of chloroform. The chloroform solution was filtered to remove the insoluble material and dried over anhydrous sodium sulfate. Addition of 150 ml of ethyl ether to the chloroform solution resulted in a precipitate which was separated by decantation and purified by reprecipitation with ethanol-ethyl ether to give 2.31 g (72 percent) of N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester. For analysis of the product, a portion of the product was converted to the flavianate; M.P. 225°-227° C, I.R. (KBr): 3,375, 3,200, 1,742 cm⁻¹.

Analysis -- Calcd. for C₂₅ H₃₇ N₅ O₈ S.C₁₀ H₆ N₂ O₈ S (percent): C, 47.67; H, 4.92; N, 11.12 Found (percent): C, 47.62; H, 4.84; N, 11.18

B. N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine was obtained in the form of an amorphous solid in a manner similar to that described in Example 3 (E). I.R. (KBr): 3,360, 3,180, 1,610 cm⁻¹.

EXAMPLE 5 A. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine

N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzyl ester was prepared by the procedure described in Example 3, and has a melting point of 133°-5° C. To a solution of 3.00 g of N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200 - 300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.71 g (70%) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine as an amorphous solid. I.R. (KBr): 3,360, 3,200, 1,590 cm⁻¹

Analysis -- Calcd. for C₂₈ H₃₅ N₅ O₇ S (percent): C, 57.42; H, 6.02; N, 11.97 Found (percent): C, 57.09; H, 6.06; N, 11.74

EXAMPLE 6 A. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride

A suspension of 2.00 g of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride.

B. N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride

A mixture of 2.00 g of m-cresol and N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride obtained above was heated at 90° C for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether to give 2.12 g (86 percent) of N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride in the form of a powder. I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm⁻¹.

The following compounds are prepared in a similar manner:

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine phenyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine benzyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine phenyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-furfurylglycine benzyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine phenyl ester

Phenyl 1-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylate

Benzyl 1-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylate

Benzyl 1-[N² -(6-chloro-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylate

Ethyl 4-[N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl]morpholine-3-carboxylate

Various other N² -arylsulfonyl-L-argininamides or salts thereof were synthesized in accordance with the procedure of the above examples, and the test results are summarized in Table 2.

EXAMPLE 7

Tablets suitable for oral administration Tablets containing the ingredients indicated below may be prepared by conventional techniques.

    ______________________________________                                                               Amount per tablet                                        Ingredient            (mg)                                                     ______________________________________                                         N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-                                                             250                                                      L-arginyl-N-(2-methoxyethyl)glycine                                            Lactose               140                                                      Corn starch           35                                                       Talcum                20                                                       Magnesium stearate    5                                                        Total                 450 mg                                                   ______________________________________                                    

EXAMPLE 8

Capsules for oral administration Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                                                               Amount per capsule                                       Ingredient            (mg)                                                     ______________________________________                                         N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-                                                             250                                                      L-arginyl-N-(2-methoxyethyl)glycine                                            Lactose               250                                                      Total                 500 mg                                                   ______________________________________                                    

EXAMPLE 9

Sterile solution for infusion The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized.

    ______________________________________                                         Ingredients            Amount (g)                                              ______________________________________                                         N.sup.2 -(7-methoxy-2-naphthylsulfonyl-                                                               25                                                      L-arginyl-N-(2-methoxyethyl)glycine                                            Buffer system          As desired                                              Glucose                25                                                      Distilled water        500                                                     ______________________________________                                    

APPENDIX

There are now described in greater detail preparation of materials of the kind used in the foregoing examples.

PREPARATION A Arylsulfonyl chlorides A. Sodium 6,7-dimethoxy-2-naphthalenesulfonate

To a well stirred solution of 70.8 g of 6,7-dihydroxy-2-naphthalenesulfonate and 77.2 g of sodium hydroxide in 450 ml of water was added dropwise 230 ml of dimethyl sulfate at 60° C over a period of 1 hour, during which time the product precipitated. To this reaction mixture was added in portions 38.8 g of sodium hydroxide, and stirring was continued for one hour. After one hour at room temperature, the precipitate was filtered, washed with ethanol and dried to give 50 g of sodium 6,7-dimethoxy-2-naphthalenesulfonate.

B. 6,7-dimethoxy-2-naphthalenesulfonyl chloride

To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1l of ice water, and the precipitate filtered and then dissolved into 250 ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo, and the residue was recrystallized from benzene-n-hexane (1 : 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P. 127.5° - 129.5° C

Analysis - Calcd. for C₁₂ H₁₁ O₄ SCl (percent): C, 50.26; H, 3.87; Cl, 12.37 Found (percent): C, 50.45; H, 4.00: Cl, 12.33.

The following arylsulfonyl chlorides not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as described in E. H. Rodd, "Chemistry of Carbon Compounds", Elsevier Publishing Company, 1954, Vol III, P. 441 - 469.

    ______________________________________                                         No.  Arylsulfonyl Chloride    M.P. (° C)                                ______________________________________                                               ##STR752##              118-119.5                                        2                                                                                    ##STR753##              136.5-138.5                                      3                                                                                    ##STR754##              137-139                                          ______________________________________                                    

preparation b amino acid derivatives A. N-butylglycine tert-butyl ester

To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional 1 hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.0 g (90.9 percent) of N-butylglycine tert-butyl ester, B.P. 76° C/4 mmHg. The following amino acid tert-butyl esters not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by A. J. Speziale et al., J. Org. Chem. 25 731 (1960).

    ______________________________________                                         No.  Amino Acid Derivative                                                                               B.P.                                                 ______________________________________                                               ##STR755##        95° C/20 mmHg                                   2                                                                                    ##STR756##        65° C/5 mmHg                                    3                                                                                    ##STR757##        89-90° C/2.5 mmHg                               4                                                                                    ##STR758##        83-5° C/1.5 mmHg                                5                                                                                    ##STR759##        125-130° C/4 mmHg                               6                                                                                    ##STR760##        61-2° C/2 mmHg                                  7                                                                                    ##STR761##        94° C/3 mmHg                                    8                                                                                    ##STR762##        60-3° C/3 mmHg                                  9                                                                                    ##STR763##        95-7° C/5 mmHg                                  10                                                                                   ##STR764##        102° C/4 mmHg                                   11                                                                                   ##STR765##        166° C/10 mmHg                                  12                                                                                   ##STR766##        106-9° C/1.5 mmHg                               13                                                                                   ##STR767##        97° C/2.5 mmHg                                  14                                                                                   ##STR768##        101° C/5 mmHg                                   15                                                                                   ##STR769##        101° C/5 mmHg                                   16                                                                                   ##STR770##        105° C/4 mmHg                                   17                                                                                   ##STR771##        129-130° C/8 mmHg                               18                                                                                   ##STR772##        145° C/15 mmHg                                  19                                                                                   ##STR773##        156° C/10 mmHg                                  20                                                                                   ##STR774##        93° C/26 mmHg                                   21                                                                                   ##STR775##        110° C/27 mmHg                                  22                                                                                   ##STR776##        124° C/26 mmHg                                  23                                                                                   ##STR777##        88-90° C/6 mmHg                                 24                                                                                   ##STR778##        116-8° C/2 mmHg                                 25                                                                                   ##STR779##        167° C/16 mmHg                                  26                                                                                   ##STR780##        125° C/16 mmHg                                  27                                                                                   ##STR781##        141° C/15 mmHg                                  28                                                                                   ##STR782##        89° C/3 mmHg                                    29                                                                                   ##STR783##        111° C/1 mmHg                                   30                                                                                   ##STR784##        91-2° C/1 mmHg                                  31                                                                                   ##STR785##        115°  C/2 mmHg                                  32                                                                                   ##STR786##        82-84° C/2 mmHg                                 33                                                                                   ##STR787##        150° C/0.5 mmHg                                 34                                                                                   ##STR788##        95-6° C/2 mmHg                                  35                                                                                   ##STR789##                                                               ______________________________________                                    

b. n-(2-methoxyethyl)glycine ethyl ester

To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1l of benzene was added dropwise a solution of 334.0 g of ethyl bromoacetate in 200 ml of benzene in one hour at room temperature. At the end of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide was removed by filtration and washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P. 73°-5° C/4 mmHg. The following amino acid ethyl esters not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by A. J. Speziale et al., J. Org. Chem., 25 731 (1960).

    ______________________________________                                                                 M.P. (° C) or B.P.                              No.  Amino Acid Ethyl Ester                                                                            (° C/mmHg)                                      ______________________________________                                               ##STR790##        57-8° C/3 mmHg                                  2                                                                                    ##STR791##        63-4° C/3 mmHg                                  3                                                                                    ##STR792##        91-3° C/2 mmHg                                  4                                                                                    ##STR793##        101-2° C                                        5                                                                                    ##STR794##        113-6° C/3 mmHg                                 6                                                                                    ##STR795##        116-7° C/1 mmHg                                 7                                                                                    ##STR796##        78-80° C/2 mmHg                                 8                                                                                    ##STR797##        63-4° C                                         ______________________________________                                    

c. n-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate

To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-6° C.

The following amino acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were synthesized by the aforementioned procedure.

    ______________________________________                                                 Amino Acid Benzyl Ester                                                No.     p-Toluenesulfonate    M.P. (° C)                                ______________________________________                                                  ##STR798##            97-9                                            2                                                                                       ##STR799##           122-4                                            3                                                                                       ##STR800##            94-5                                            4                                                                                       ##STR801##            66-8                                            5                                                                                       ##STR802##           101-2                                            6                                                                                       ##STR803##           140-3                                            7                                                                                       ##STR804##           154-6                                            8                                                                                       ##STR805##           133-5                                            9                                                                                       ##STR806##           133-5                                            10                                                                                      ##STR807##           133-8                                            11                                                                                      ##STR808##           103-6                                            12                                                                                      ##STR809##            92-4                                            13                                                                                      ##STR810##           123-6                                            14                                                                                      ##STR811##           119-123                                          15                                                                                      ##STR812##           130-1                                            ______________________________________                                    

preparation c 2-piperidinecarboxylic acids and esters thereof A. 4-methyl-2-piperidinecarbonitrile

To 500 g of 10% sodium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine acetate in 10 ml of water over a period of 1 hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sulfate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 mole) of potassium hydroxide in 100mls of 95% ethanol under reflu. Refluxing was continued for an additional 10 minutes. Ethanol was evaporated, and the residue was dissolved into 50 ml of 2N sodium hydroxide solution and then extracted with ether.

The ether layer was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an ice-cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at a temperature of 10 to 20° C for 4 hours and thereafter made basic by the addition of solid sodium hydroxide. The reaction product was extracted with ether, dried over anhydrous sodium sulfate and then distilled under reduced pressure to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P. 96°-97° C/10 mmHg.

The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by Grundon et at., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., 1964, 2448, R. Bonnett et al., J. Chem. Soc., 1959, 2092 and II. Bohme et al., Ber., 92 1613 (1959).

    ______________________________________                                          ##STR813##                                                                    No.        R.sub.7          B.P.                                               ______________________________________                                         1        4-CH.sub.2 CH.sub.3                                                                             105-106° C/9 mmHg.                            2        4-CH.sub.2 CH.sub.2 CH.sub.3                                                                    116° C/8 mmHg.                                          ##STR814##      104° C/4 mmHg.                                4        2-CH.sub.3                                                            ______________________________________                                    

b. 4-methyl-2-piperidinecarboxylic acid hydrochloride

A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6N hydrochloric acid was refluxed for 6 hours. After evaporation of the solvent, the residue was recrystallised from water to give 13 g of 4-methyl-2-piperidinecarboxylic acid hydrochloride.

C. Ethyl 4-methyl-2-piperidinecarboxylate

A solution of 13 g (0.072 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this period, the solvent was evaporated under reduced pressure, and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7.4 g (60%) of ethyl 4-methyl-2-piperidinecarboxylate, B.P. 76-77° C/3 mmHg.

D. Benzyl 4-methyl-2-piperdinecarboxylate p-toluenesulfonate

A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylic p-toluenesulfonate, M.P. 160°-163° C.

The following 2-piperidinecarboxylates not previously reported in the chemical literature were synthesized by the afoementioned procedure.

    ______________________________________                                          ##STR815##                                                                                       Addition                                                    No.      R.sub.7   moiety     B.P.                                             ______________________________________                                         1      4-CH.sub.2 CH.sub.3                                                                        --         82-4° C/3.5 mmHg                          2      4-CH.sub.2 CH.sub.2 CH.sub.3                                                               HCl                                                                 ##STR816## --         95-6° C/2 mmHg                            4      2-CH.sub.3  --         57° C/3 mmHg                              ______________________________________                                    

Morpholine-3-carboxylic acid hydrochloride was prepared by the procedure described above, and has a melting point of 200°-2° C.

The following starting materials for the preparation of the N² -arylsulfonyl-L-argininamides were prepared by the procedures described in the following literatures:

    ______________________________________                                         Compound        Literature                                                     ______________________________________                                          ##STR817##     J. Org. Chem., 29 2203 (1964)                                   ##STR818##     J. Org. Chem., 29 2203 (1964)                                   ##STR819##     J. Am. Chem. Soc., 59 200 (1937)                                ##STR820##     Zh. Obshch. Khim., 9 2245 (1973)                                ##STR821##     Ber., 44 2034 (1911)                                            ##STR822##     Ber., 65 927 (1932)                                            ______________________________________                                    

The methyl or ethyl ester of the aforementioned compounds were prepared by a conventional esterification procedure. Ethyl thiomorpholine-3-carboxylate has a boiling point of 108° C/4 mmHg.

Diethyl piperidine-2,6-dicarboxylate hydrochloride was prepared by the conventional esterification of piperidine2,6-dicarboxylic acid and has a melting point of 184°-6° C. lsoindoline-1-carboxylic acid was prepared by a procedure similar to that for the preparation of isoquinoline-3-carboxylic acid described in Ber., 44 2034 (1911). Ethyl isoindoline-1-carboxylate hydrochloride was prepared by the conventional esterification of isoindoline-1-carboxylic acid and has a melting point of 139°-140.5° C. Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit of the invention as set forth herein. 

What is claimed as new and desired to be secured by letters patent of the United States is:
 1. An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR823## or a pharmaceutically acceptable salt thereof, wherein R is ##STR824## wherein R₁ is --COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 to 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -C₂₀ dialkylamino, and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₀ aralkyl, carbonyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydoxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof; naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;
 5. 6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;C₇ -c₁₂ aralkyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl or isoindolinyl, group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoy, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, metcapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C;hd 1-C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, αs-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, IH-indazolyl, 1,8-naphthyridinyl, carbazolyl, or benzimidazolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamic, carbamoyl, C₃ -C₁₀ N,N-dalkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ ;l hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.
 2. An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR825## or a pharmaceutically acceptable salt thereof, wherein R is ##STR826## wherein R₁ is --COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 or 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;and Ar is naphthyl substituted with at least one subitituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -C₁₀ dialkylamino, and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof; naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ hydroxylalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, _(C) ₂ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxylakyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;
 5. 6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxcarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;C₇ -c₁₂ aralkyl-9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthyryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrogenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxylphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl or isoindolinyl, any of wich is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.
 3. The compound of claim 1, wherein said Ar group is substituted with at least one C₁ -C₅ alkoxy, C₁ -C₅ alkyl group or mixtures thereof.
 4. The compound of claim 2, wherein said phenyl group is substituted with at least one C₁ -C₅ alkoxy group.
 5. A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim
 1. 6. A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim
 2. 